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US20050181034A1 - Formulation of liposomal derivatives of phenylalanine - Google Patents

Formulation of liposomal derivatives of phenylalanine Download PDF

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Publication number
US20050181034A1
US20050181034A1 US10/521,805 US52180505A US2005181034A1 US 20050181034 A1 US20050181034 A1 US 20050181034A1 US 52180505 A US52180505 A US 52180505A US 2005181034 A1 US2005181034 A1 US 2005181034A1
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Prior art keywords
formulation
weight
liposomes
active ingredient
proportion
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Abandoned
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US10/521,805
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English (en)
Inventor
Katja Wosikowski-Buters
Wolfgang Schmalix
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Heidelberg Pharma AG
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Wilex AG
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Assigned to WILEX AG reassignment WILEX AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHMALIX, WOLFGANG, WOSIKOWSKI-BUTERS, KATJA
Publication of US20050181034A1 publication Critical patent/US20050181034A1/en
Assigned to WILEX AG reassignment WILEX AG CHANGE OF ADDRESS WITH TRANSLATION Assignors: WILEX AG
Assigned to WILEX AG reassignment WILEX AG RE-RECORD TO CORRECT PROPERTY NUMBER ON A DOCUMENT PREVIOUSLY RECORDED AT REEL 022127, FRAME 0451. (ASSIGNMENT OF ASSIGNOR'S INTEREST) Assignors: WILEX AG
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to pharmaceutical formulations of phenylalanine derivatives and to the use thereof as urokinase inhibitors, in particular for the treatment of malignant tumors and of tumor metastases.
  • uPA plasminogen activator urokinase
  • uPAR urokinase receptor
  • Plasmin in turn is a protease with a wide range of effects which is able to break down components of the extracellular matrix such as fibrin, fibronectin, laminin and the protein framework of the proteoglycans directly.
  • plasmin can activate “latent” metalloproteases and the inactive proenzyme of uPA, pro-uPA.
  • Tumor cells and nonmalignant cells of the tumor stroma synthesize and secrete the enzymatically inactive proenzyme pro-uPA.
  • pro-UPA and the active protease HMW-uPA bind to the cell surface receptor uPAR (CD87).
  • Plasmin(ogen) likewise binds to specific receptors on the plasma membrane of the tumor cell, thus achieving focusing and amplification of plasminogen activation in the immediate surroundings of the tumor cell. Invasive cells are thus enabled to break down the extracellular matrix without evading the bases necessary for directed movement through proteolysis.
  • 3-amidinophenylalanine derivatives substituted in position 2 by a phenyl radical are selective uPA inhibitors which are active in vivo (PCT/EP99/05145). These compounds are administered in animal experiments in the form of aqueous solutions.
  • DE 102 25 876.7 discloses the use of 3-guanidinophenylalanine derivatives as urokinase inhibitors.
  • the object on which the invention is based was thus to provide pharmaceutical formulations with a urokinase inhibitor derived from 3-amidinophenylalanine or 3-guanidinophenylalanine, which, on the one hand, have high activity and, on the other hand, are stable and tolerated.
  • the present invention relates in particular to novel urokinase inhibitors derived from 3-amidinophenylalanine or 3-guanidinophenylalanine, of the general formula I which are in the form of racemates and as compounds having the L or D configuration, and in which
  • the compounds may also be in the form of salts, preferably physiologically tolerated acid salts, e.g. salts of mineral acids, particularly preferably hydrochlorides, or salts of suitable organic acids.
  • physiologically tolerated acid salts e.g. salts of mineral acids, particularly preferably hydrochlorides, or salts of suitable organic acids.
  • R 1 corresponds to a group of the formulae (b), (d) and (f)
  • R 2 is a mono-, bi- or tri-alkyl-substituted phenyl radical, in particular a 2,4,6-substituted phenyl radical, e.g. a 2,4,6-triisopropylphenyl radical, and n is 0, are particularly important.
  • Compounds in which Z is CH or N are further preferred.
  • the compound of the formula (I) is particularly preferably N ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(D,L)-phenylalanine 4-ethoxycarbonylpiperazide, N ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-guanidino-(D,L)-phenylalanine 4-ethoxycarbonylpiperazide or the L enantiomer thereof or a pharmaceutically acceptable salt of these compounds.
  • the compounds of the invention are able to inhibit highly efficiently the growth or/and the dissemination of malignant tumors, e.g. tumor dissemination in cases of pancreatic carcinoma, tumor growth of carcinoma of the breast, and the metastasis of tumors.
  • the uPA inhibitors can moreover be employed where appropriate together with other antitumor agents or with other modes of treatment, e.g. radiation or surgical procedures.
  • the inhibitors of the invention are also effective for other uPA-associated disorders (e.g. for preventing the formation of blisters associated with the skin disease pemphigus vulgaris).
  • the liposomal formulations of the invention comprise the active ingredient preferably in a proportion by weight of 0.5-10%, particularly preferably of 2-5%, based on the total weight of the formulation. It is further preferred for the formulation—at least its aqueous component—to have a pH in the range 5.5-9.0.
  • the content of free active ingredient, i.e. that present after removal of lipid components by filtration in the aqueous phase of the formulation, is preferably ⁇ 1 mg/ml, particularly preferably ⁇ 500 ⁇ g/ml and most preferably ⁇ 100 ⁇ g/ml.
  • the formulation preferably comprises phospholipids in a proportion by weight of 4.5-40%, particularly preferably of 6-15%, based on the total weight of the formulation.
  • suitable phospholipids are neutral phospholipids such as, for example, phosphatidylcholine, anionic phospholipids such as, for example, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphoinositol and esterified derivatives thereof, such as, for example, dimyristoylphosphatidylglycerol.
  • the formulation particularly preferably comprises at least one anionic phospholipid. Good results have been obtained on use of a combination of phosphatidylcholine and dimyristoylphosphatidylglycerol in a ratio of 70:30 by weight.
  • the formulation may preferably comprise a membrane-stabilizing component such as, for example, cholesterol or derivatives thereof, in a proportion by weight of up to 5% based on the total weight of the formulation.
  • a membrane-stabilizing component such as, for example, cholesterol or derivatives thereof, in a proportion by weight of up to 5% based on the total weight of the formulation.
  • the membrane stability or rigidity can, however, also be adjusted by the selection of appropriate fatty acids in the phospholipids or, where appropriate, other lipid components via the chain length or/and the degree of unsaturation.
  • the formulation preferably also comprises a cryoprotectant which is beneficially present in a proportion by weight of up to 15%, preferably of 5-15%, based on the total weight of the formulation.
  • cryoprotectants are carbohydrates, e.g. mono-, di- or trisaccharides, such as, for example, lactose, sucrose, trilactose, maltose, trehalose etc. or/and sugar alcohols such as, for example, sorbitol, mannitol etc.
  • the liposomal formulation of the invention may comprise unilamellar liposomes, multilamellar liposomes, unordered complexes and combinations thereof.
  • Preferred liposomes have an average diameter after production not greater than 500 nm and, in particular, in the range 100-250 nm.
  • the liposomal formulation of the invention can be produced for example by high-pressure homogenization of a suspension comprising the active ingredient and the lipids and, where appropriate, subsequent filtration.
  • Other possibilities are known to the skilled worker, e.g. solvent injection, hydration of lipid films etc.
  • the liposomal formulation can be sterilized by filtration and, where appropriate, dehydrated, e.g. by lyophilization.
  • the average diameter may increase, e.g. to 100-1000 nm, after aqueous reconstitution of dehydrated liposomes.
  • the formulation of the invention can be employed for parenteral administration, e.g. for intravenous injection, for infusion or for subcutaneous or intramuscular injection.
  • the daily dose is preferably 5-250 mg, particularly preferably 20-120 mg on subcutaneous or intramuscular administration and 10-500 mg, particularly preferably 50-250 mg on intravenous administration, in each case based on an average body weight of 70 kg.
  • Administration preferably takes place once a day to once a week.
  • the formulation of the invention can be employed where appropriate in combination with other active ingredients, e.g. cytoxic agents. Joint administration is preferred, e.g. as treatment before or/and after surgical procedures, radiotherapy or/and chemotherapy.
  • Dimyristoylphosphatidylglycerol sodium salt (DMPG-Na) was purchased from Nippon Fine Chemicals.
  • Egg phosphatidylcholine (EPC) was purchased from Lipoid KG.
  • the phospholipids and the active ingredient N ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine 4-ethoxycarbonylpiperazide (WX-UK1) as hydrochloride were dispersed together in 50 mmol/l phosphate buffer of pH 6.5 and 9% lactose. The mixture was then heated to 40° C. and put in an ultrasonic bath for 30 min.
  • EmulsiFlex C5 apparatus from Avestin equipped with an extrusion unit, was used for the high-pressure homogenization so that it was possible to carry out homogenization and high-pressure extrusion through a polycarbonate membrane filter in series.
  • the liposome suspension was passed through the high-pressure homogenizer for 6 min (corresponding to 20 passages) under a pressure of 345 bar.
  • the formulation was then passed for 6 min through a 100 nm polycarbonate membrane filter in the extrusion unit.
  • Liposomal preparations with a pH of 8.4 were obtained in a similar way. Firstly, however, a dispersion with a pH of 5.2 was prepared and subjected to a high-pressure homogenization. The pH was then adjusted to 8.4 by adding disodium hydrogen phosphate, and a further homogenization was carried out for 6 min under a pressure of 345 bar.
  • the liposomal formulations were filtered through a sterilized 450 nm filter (Durapore polyvinylidene difluoride from Millipore), and the filtered suspensions were filled in 0.5 ml aliquots and then lyophilized.
  • a sterilized 450 nm filter Durapore polyvinylidene difluoride from Millipore
  • the average size and the size distribution of the liposomal suspensions were determined using a Malvern Zetasizer 1000.
  • the degree of homogeneity of the suspensions has been expressed as polydispersity index (PI).
  • PI polydispersity index
  • a value of 0.1 means a very narrow size distribution and a value of 0.9 a very wide distribution.
  • compositions and the results of analysis are summarized in Table 1 below.
  • the active ingredient content of the liposomal formulation was between 18 and 21 mg/ml and the particle size was between 350 and 500 nm, there having been a significant increase in the particle size during the lyophilization and reconstitution.
  • mice Female wistar rats, 240-300 g body weight (Charles River-Wiga, Sulzfeld), were treated with the active ingredient WX-UK1 in the form of an aqueous solution or with the liposomal formulations 1-4 described in Example 1.
  • the animals each received 1 dose/day over a period of 10 days.
  • the administrations took place in the region of the flank (between shoulder and rear limbs) so that the animals were unable to reach the injection site with their paws.
  • the injection sites were approx. 1 cm apart, no site being injected more than once.
  • the first five injections took place on the left side, and the second five injections on the right side.
  • the dose was usually 3 mg of active ingredient/kg of body weight, i.e. 0.9 mg of active ingredient was administered for an average body weight of 300 g.
  • Radiolabeled active ingredient (3H-WX-UK1) was administered in some cases.
  • the animals were weighed before each injection and observed for 2 h after each injection, and before each further injection the previous injection sites were palpated. The behavior of the animals and the palpation findings were recorded.
  • the animals were anaesthetized (ethylurethane, 1.4 g/kg i.p.), and citrated blood was obtained from the retroorbital venous plexus; citrated plasma was obtained by centrifugation at 1200 ⁇ g for 10 min. The bile duct was then dissected, and bile was obtained for 15 min. Subsequently, the areas of skin at the injection sites were examined and the growth findings on dissection were recorded.
  • the animals were then sacrificed, and various organs (heart, kidney, liver, spleen) were dissected.
  • the active ingredient content in the plasma, bile and organs was determined by HPLC [standard method using Nucleosil 7 C18 columns (Macherey-Nagel, Düren), acetonitrile/water/perchloric acid 30/70/0.04, 1 ml/min] after prepurification using Chromabond C18 solid-phase extraction columns (Macherey-Nagel, Duren).
  • HPLC standard method using Nucleosil 7 C18 columns (Macherey-Nagel, Düren), acetonitrile/water/perchloric acid 30/70/0.04, 1 ml/min] after prepurification using Chromabond C18 solid-phase extraction columns (Macherey-Nagel, Duren).
  • 3 H-WX-UK1 was used, the active ingredient concentration was determined immediately after lyophilization of the samples by measuring the radioactivity in
  • Lyophilized neutral liposomes of pH 6.5 (formulation 1) were resuspended with water and employed directly. In accordance with the concentration of 20 mg/ml which was then present, 45 ⁇ l were administered per rat (300 g body weight), which corresponds to the desired dose of 3 mg/kg of body weight (experiments 624, 625).
  • Lyophilized negative liposomes of pH 6.5 (formulation 2) were resuspended with water. In accordance with the concentration of 16 mg/ml then present, 55 ⁇ l were administered per rat (300 g body weight), which corresponds to the desired dose of 3 mg/kg of body weight (experiments 626, 627).
  • Lyophilized neutral liposomes of pH 8.4 (formulation 3) were resuspended with water and employed directly. In accordance with the concentration of 20 mg/ml which was then present, 45 ⁇ l were administered per rat (300 g body weight), which corresponds to the desired dose of 3 mg/kg of body weight (experiments 632, 633).
  • Lyophilized negative liposomes of pH 8.4 (formulation 4) were resuspended with water and employed directly. In accordance with the concentration of 20 mg/ml then present, 45 ⁇ l were administered per rat (300 g body weight), which corresponds to the desired dose of 3 mg/kg of body weight (experiments 637, 638).
  • Table 2 contains the concentrations of WX-UK1 in plasma, bile and the organs kidney, liver, spleen and heart. The concentration in the plasma could be determined only by using 3 H-WX-UK1 and is ⁇ 100 ng/ml. Very comparable concentrations are found in the controls with administrations in NaCl/ethanol and administration of liposomes 3 and 4. Lower concentrations of WX-UK1 were found in bile and organs with liposomes 1 and 2. Table 2 is a compilation of the assessment of the histological findings.
  • Tables 3 and 4 contain the assessment of the consequences of administration to the animals. It is evident that administration of the liposomal formulations leads to considerably milder side effects than administration of the aqueous solution.
  • FIG. 1 (magnification 25 ⁇ ) depicts skin after administration after WX-UK1 dissolved in liposomes 4. No changes from normal skin ( FIG. 2 ) are evident.
  • the active ingredient formulations were administered subcutaneously. Administration took place in the region of the neck of two rabbits and into the flank of a further two rabbits. Each animal received four subcutaneous injections per administration day with an interval of 2 days on study days 1, 3, 5 and 7. The volume of the formulation administered was between 0.41 and 0.5 ml/administration.
  • Liposomal formulations 1-4 described in Example 1 were administered. No local intolerance reactions at all were found therewith. There were no signs of edema, erythema, necrotic changes or mechanical changes (scratching).
  • the pharmacological activity of the liposomal formulations of the invention was tested on female rats (age 7 weeks, weight 100-150 g).
  • Group D liposomal formulation 4 (PC/PG pH 8.4), 1.0 mg of active ingredient/kg, 1 ⁇ /day s.c.
  • Group E liposomal formulation 4 (PC/PG pH 8.4), 3.0 mg of active ingredient/kg, 1 ⁇ /day s.c.
  • the occurrence of tumor foci in the lung, in the axillary lymph nodes and in the intraperitoneal lymph nodes, and the weight of the tumors were determined.
  • the intention was to test whether liposomal WX-UK1 formulations are able to reduce hemolytic properties of the active ingredient.
  • the hemolysis test was carried out in parallel with diluted whole blood and washed erythrocytes, in each case in duplicate.
  • 1 ml of blood (stabilized with citrate) was diluted with 4 ml of 0.9% strength NaCl solution and divided into aliquots each of 200 ⁇ l.
  • 1 ml of the respectively tested active ingredient solution 600, 240, 120, 60, 24, 12, 0 ⁇ g/ml based on the active ingredient content
  • the liposomal formulations tested were formulations 1 (EPC, pH 6.5) and 2 (PC/PG, pH 6.5) according to Example 1. Only with the highest concentration (500 ⁇ g) of formulation 1 was a weak hemolysis found in whole blood. All the higher dilutions were non-hemolytic. Formulation 2 was not hemolytic for any of the tested concentrations with whole blood or washed erythrocytes.
  • 60 ⁇ l of the formulation were centrifuged through a Microcon YM-50 filter unit and then investigated for the content of remaining active ingredient in an HPLC with the aid of a calibration line.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US10/521,805 2002-07-24 2003-07-22 Formulation of liposomal derivatives of phenylalanine Abandoned US20050181034A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10233632A DE10233632A1 (de) 2002-07-24 2002-07-24 Formulierungen von Phenylalanin-Derivaten
DE10233632.6 2002-07-24
PCT/EP2003/008011 WO2004011004A1 (fr) 2002-07-24 2003-07-22 Formulations liposomales de derives de phenylalanine

Publications (1)

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US20050181034A1 true US20050181034A1 (en) 2005-08-18

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US10/521,805 Abandoned US20050181034A1 (en) 2002-07-24 2003-07-22 Formulation of liposomal derivatives of phenylalanine

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US (1) US20050181034A1 (fr)
EP (1) EP1534283B1 (fr)
AT (1) ATE312610T1 (fr)
AU (1) AU2003251446A1 (fr)
DE (2) DE10233632A1 (fr)
ES (1) ES2250918T3 (fr)
WO (1) WO2004011004A1 (fr)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186183A (en) * 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4906477A (en) * 1987-02-09 1990-03-06 Kabushiki Kaisha Vitamin Kenkyusyo Antineoplastic agent-entrapping liposomes
US5023087A (en) * 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system
US5049392A (en) * 1989-01-18 1991-09-17 The Liposome Company, Inc. Osmotically dependent vesicles
US5660822A (en) * 1990-05-14 1997-08-26 University Of Medicine & Dentistry Of N.J. Polymers containing antifibrotic agents, compositions containing such polymers, and methods of preparation and use
US5776486A (en) * 1993-05-28 1998-07-07 Aphios Corporation Methods and apparatus for making liposomes containing hydrophobic drugs
US5817334A (en) * 1988-10-05 1998-10-06 Nexstar Pharmaceuticals, Inc. Method of making liposomes with improved stability during drying
US6010890A (en) * 1997-04-29 2000-01-04 New York Blood Center, Inc. Method for viral inactivation and compositions for use in same
US6156337A (en) * 1994-07-08 2000-12-05 Opperbas Holding B.V. Method for high loading of vesicles with biopolymeric substances
US6168778B1 (en) * 1990-06-11 2001-01-02 Nexstar Pharmaceuticals, Inc. Vascular endothelial growth factor (VEGF) Nucleic Acid Ligand Complexes
US20030013723A1 (en) * 1998-07-20 2003-01-16 Wilex Ag Novel urokinase inhibitors
US6599527B1 (en) * 1997-06-20 2003-07-29 Phares Pharmaceutical Research N.V. Preparation of pharmaceutical compositions
US6716963B1 (en) * 1998-05-22 2004-04-06 Abbott Laboratories Peptide antiangiogenic drugs

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19940389A1 (de) * 1999-08-25 2001-03-01 Wilex Biotechnology Gmbh Selektive Inhibitoren des Urokinase-Plasminogen Aktivators
DE10013715A1 (de) * 2000-03-20 2001-09-27 Wilex Biotechnology Gmbh Hochselektive Inhibitoren des Urokinase-Plasminogenaktivators

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186183A (en) * 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US5023087A (en) * 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system
US4906477A (en) * 1987-02-09 1990-03-06 Kabushiki Kaisha Vitamin Kenkyusyo Antineoplastic agent-entrapping liposomes
US5817334A (en) * 1988-10-05 1998-10-06 Nexstar Pharmaceuticals, Inc. Method of making liposomes with improved stability during drying
US5049392A (en) * 1989-01-18 1991-09-17 The Liposome Company, Inc. Osmotically dependent vesicles
US5660822A (en) * 1990-05-14 1997-08-26 University Of Medicine & Dentistry Of N.J. Polymers containing antifibrotic agents, compositions containing such polymers, and methods of preparation and use
US6168778B1 (en) * 1990-06-11 2001-01-02 Nexstar Pharmaceuticals, Inc. Vascular endothelial growth factor (VEGF) Nucleic Acid Ligand Complexes
US5776486A (en) * 1993-05-28 1998-07-07 Aphios Corporation Methods and apparatus for making liposomes containing hydrophobic drugs
US6156337A (en) * 1994-07-08 2000-12-05 Opperbas Holding B.V. Method for high loading of vesicles with biopolymeric substances
US6010890A (en) * 1997-04-29 2000-01-04 New York Blood Center, Inc. Method for viral inactivation and compositions for use in same
US6599527B1 (en) * 1997-06-20 2003-07-29 Phares Pharmaceutical Research N.V. Preparation of pharmaceutical compositions
US6716963B1 (en) * 1998-05-22 2004-04-06 Abbott Laboratories Peptide antiangiogenic drugs
US20030013723A1 (en) * 1998-07-20 2003-01-16 Wilex Ag Novel urokinase inhibitors

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Publication number Publication date
DE50301954D1 (de) 2006-01-19
WO2004011004A1 (fr) 2004-02-05
AU2003251446A1 (en) 2004-02-16
EP1534283B1 (fr) 2005-12-14
EP1534283A1 (fr) 2005-06-01
ATE312610T1 (de) 2005-12-15
DE10233632A1 (de) 2004-02-05
ES2250918T3 (es) 2006-04-16

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